Tudor domain

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TUDOR domain
PDB 2diq EBI.jpg
Structure of a TUDOR domain.
Identifiers
SymbolTUDOR
Pfam PF00567
Pfam clan CL0049
InterPro IPR008191
SMART TUDOR
PROSITE PDOC50304
SCOP2 3fdr / SCOPe / SUPFAM
CDD cd04508

In molecular biology, a Tudor domain is a conserved protein structural domain originally identified in the Tudor protein encoded in Drosophila. [1] The Tudor gene was found in a Drosophila screen for maternal factors that regulate embryonic development or fertility. [2] Mutations here are lethal for offspring, inspiring the name Tudor, as a reference to the Tudor King Henry VIII and the several miscarriages experienced by his wives. [1]

Contents

Structure

A Tudor domain is a protein region approximately 60 amino acids in length, which folds into an SH3-like structure with a five-stranded antiparallel beta-barrel form. [1] Tudor domains can further be organized into functional units consisting of either a single Tudor domain, tandem Tudor domains, or hybrid Tudor domains consisting of two Tudor domains linked by an anti-parallel beta-sheet made from their shared second and third beta-strands. [1] An essential component of the Tudor domain structure is the aromatic-binding cage formed by several (typically 4–5) aromatic amino acid residues. [1]

Interaction with methylated residues

Tudor domains exert their functions by recognizing and binding methylated lysine and arginine residues, allowing them to function as histone readers in an epigenetic context. [1] This occurs through cation–pi interactions between the methylated Arg/Lys residue and the aromatic residues of the Tudor domain's aromatic-binding cage. [1] Depending on the Tudor domain, this interaction can be methylation state-specific (mono-, di-, or trimethylation). [1]

Function

DNA transcription and modification

Tudor domain proteins are involved in epigenetic regulation and can alter transcription by recognizing post-translational histone modifications and as adaptor proteins. [2] Recognition of methylated arginine and lysine histone residues results in the recruitment of downstream effectors, leading to chromatin silencing or activation depending on the Tudor domain protein and context. [1] For example, the human TDRD3 protein binds methylated arginine residues and promotes transcription of estrogen-responsive elements. [3] Conversely, the Polycomb-like protein (PCL) acts as an adaptor to recruit components of the Polycomb repressive complex 2 (PRC2), a histone H3K27 methyltransferase that represses transcription. [4] Additionally, Tudor domain proteins can repress transcription by recruiting DNA-methyltransferases to promote DNA methylation and heterochromatin assembly. [1] Tudor domain proteins also have the function of maintaining and propagating epigenetic modifications. [1]

Genome stability

The Tudor domain is involved in the silencing of selfish genetic elements, such as retrotransposons. [5] This functionality is performed both directly through Tudor-containing proteins, such as Tdrd7, as well as through piRNA synthesis. [6] Tudor domains are essential in the localization of protein machinery involved in piRNA creation, such as localization of Yb protein to the Yb body, assembly of the pole plasm in Drosophila, and recruitment of proteins to load Piwi with piRNA. [5]

DNA damage response

The human p53-binding protein 1 (TRP53BP1) is a Tudor domain protein involved in the DNA damage response (DDR) pathway, which functions to protect the genome from external stimuli. [5] It is a cascade of events that senses damage through adaptor proteins and triggers responses including cell cycle arrest, DNA repair, transcriptional modifications, and apoptosis. [5] TRP53BP1s Tudor domain mediates binding to sensors that accumulate at the sites of damage, and also functions as the adaptor promoting effector recruitment to the damaged sites. [5] TRP53BP1 is essential for DDR as it plays a very complex role in the regulation and recruitment of multiple other proteins involved. [5]

RNA metabolism

Tudor domain proteins involved in RNA metabolism have an extended Tudor domain of approximately 180 amino acids. [5] These proteins contain RNA-binding motifs to target RNAs, or bind to dimethylated arginines of proteins bound to RNAs. [5] These proteins regulate multiple aspects of RNA metabolism, including processing, stability, translation, and small RNA pathways. [5] Specifically, the survival motor neuron (SMN) protein is a Tudor domain protein that mediates the assembly of snRNPs (small nuclear ribonucleoproteins), by binding snRNAs and recruiting asymmetrically dimethylated arginines of SM proteins that form the protein constituent of snRNPs. [5] SMN promotes the maturation of snRNPs, which are essential for spliceosome assembly and intron removal. [5]

Examples

Hybrid Tudor domain in JMJD2A Protein structure of JMJD2A hybrid Tudor domains.png
Hybrid Tudor domain in JMJD2A

The proteins TP53BP1 (Tumor suppressor p53-binding protein 1) and its fission yeast homolog Crb2 [8] and JMJD2A (Jumonji domain containing 2A) contain either tandem or double Tudor domains and recognize methylated histones. [9] [10]

The structurally characterized Tudor domain in human SMN (survival of motor neuron) is a strongly bent anti-parallel β-sheet consisting of five β-strands with a barrel-like fold and recognizes symmetrically dimethylated arginine. [11]

Other Tudor domain containing proteins include AKAP1 (A-kinase anchor protein 1) [12] and ARID4A (AT rich interactive domain 4A) among others. A well known Tudor domain containing protein is Staphylococcal Nuclease Domain Containing 1 (SND1)/Tudor-SN/p100 co activator. [13] SND1 is involved in RISC complex and interacts with AEG-1 oncogene. [14] SND1 is also acts as an oncogene and plays a very important role in HCC and colon cancer. [15] The SND1 Tudor domain binds to methylated arginine in the PIWIL1 protein. [16] Tudor containing SND1 promotes tumor angiogenesis in human hepatocellular carcinoma through a novel pathway which involves NF-kappaB and miR-221. [17] Tudor SND1 is also present in the Drosophila melanogaster. [6]

Related Research Articles

Histone Family proteins package and order the DNA into structural units called nucleosomes.

In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn are wrapped into 30-nanometer fibers that form tightly packed chromatin. Histones prevent DNA from becoming tangled and protect it from DNA damage. In addition, histones play important roles in gene regulation and DNA replication. Without histones, unwound DNA in chromosomes would be very long. For example, each human cell has about 1.8 meters of DNA if completely stretched out, however when wound about histones, this length is reduced to about 90 micrometers (0.09 mm) of 30 nm diameter chromatin fibers.

Histone methyltransferase

Histone methyltransferases (HMT) are histone-modifying enzymes, that catalyze the transfer of one, two, or three methyl groups to lysine and arginine residues of histone proteins. The attachment of methyl groups occurs predominantly at specific lysine or arginine residues on histones H3 and H4. Two major types of histone methyltranferases exist, lysine-specific and arginine-specific. In both types of histone methyltransferases, S-Adenosyl methionine (SAM) serves as a cofactor and methyl donor group.
The genomic DNA of eukaryotes associates with histones to form chromatin. The level of chromatin compaction depends heavily on histone methylation and other post-translational modifications of histones. Histone methylation is a principal epigenetic modification of chromatin that determines gene expression, genomic stability, stem cell maturation, cell lineage development, genetic imprinting, DNA methylation, and cell mitosis.

Histone methylation is a process by which methyl groups are transferred to amino acids of histone proteins that make up nucleosomes, which the DNA double helix wraps around to form chromosomes. Methylation of histones can either increase or decrease transcription of genes, depending on which amino acids in the histones are methylated, and how many methyl groups are attached. Methylation events that weaken chemical attractions between histone tails and DNA increase transcription because they enable the DNA to uncoil from nucleosomes so that transcription factor proteins and RNA polymerase can access the DNA. This process is critical for the regulation of gene expression that allows different cells to express different genes.

Methyltransferase Group of methylating enzymes

Methyltransferases are a large group of enzymes that all methylate their substrates but can be split into several subclasses based on their structural features. The most common class of methyltransferases is class I, all of which contain a Rossmann fold for binding S-Adenosyl methionine (SAM). Class II methyltransferases contain a SET domain, which are exemplified by SET domain histone methyltransferases, and class III methyltransferases, which are membrane associated. Methyltransferases can also be grouped as different types utilizing different substrates in methyl transfer reactions. These types include protein methyltransferases, DNA/RNA methyltransferases, natural product methyltransferases, and non-SAM dependent methyltransferases. SAM is the classical methyl donor for methyltrasferases, however, examples of other methyl donors are seen in nature. The general mechanism for methyl transfer is a SN2-like nucleophilic attack where the methionine sulfur serves as the leaving group and the methyl group attached to it acts as the electrophile that transfers the methyl group to the enzyme substrate. SAM is converted to S-Adenosyl homocysteine (SAH) during this process. The breaking of the SAM-methyl bond and the formation of the substrate-methyl bond happen nearly simultaneously. These enzymatic reactions are found in many pathways and are implicated in genetic diseases, cancer, and metabolic diseases. Another type of methyl transfer is the radical S-Adenosyl methionine (SAM) which is the methylation of unactivated carbon atoms in primary metabolites, proteins, lipids, and RNA.

Demethylases are enzymes that remove methyl (CH3-) groups from nucleic acids, proteins (in particular histones), and other molecules. Demethylase enzymes are important in epigenetic modification mechanisms. The demethylase proteins alter transcriptional regulation of the genome by controlling the methylation levels that occur on DNA and histones and, in turn, regulate the chromatin state at specific gene loci within organisms.

Methyllysine Derivative of the amino acid residue lysine where the sidechain ammonium group has been methylated one or more times.

Methyllysine is derivative of the amino acid residue lysine where the sidechain ammonium group has been methylated one or more times.

Histone-modifying enzymes

Histone-modifying enzymes are enzymes involved in the modification of histone substrates after protein translation and affect cellular processes including gene expression. To safely store the eukaryotic genome, DNA is wrapped around four core histone proteins, which then join together to form nucleosomes. These nucleosomes further fold together into highly condensed chromatin, which renders the organism's genetic material far less accessible to the factors required for gene transcription, DNA replication, recombination and repair. Subsequently, eukaryotic organisms have developed intricate mechanisms to overcome this repressive barrier imposed by the chromatin through histone modification, a type of post-translational modification which typically involves covalently attaching certain groups to histone residues. Once added to the histone, these groups elicit either a loose and open histone conformation, euchromatin, or a tight and closed histone conformation, heterochromatin. Euchromatin marks active transcription and gene expression, as the light packing of histones in this way allows entry for proteins involved in the transcription process. As such, the tightly packed heterochromatin marks the absence of current gene expression.

EZH2

Enhancer of zeste homolog 2 (EZH2) is a histone-lysine N-methyltransferase enzyme encoded by EZH2 gene, that participates in histone methylation and, ultimately, transcriptional repression. EZH2 catalyzes the addition of methyl groups to histone H3 at lysine 27, by using the cofactor S-adenosyl-L-methionine. Methylation activity of EZH2 facilitates heterochromatin formation thereby silences gene function. Remodeling of chromosomal heterochromatin by EZH2 is also required during cell mitosis.

PRMT1

Protein arginine N-methyltransferase 1 is an enzyme that in humans is encoded by the PRMT1 gene. The HRMT1L2 gene encodes a protein arginine methyltransferase that functions as a histone methyltransferase specific for histone H4.

SND1

Staphylococcal nuclease domain-containing protein 1 also known as 100 kDa coactivator or Tudor domain-containing protein 11 (TDRD11) is a protein that in humans is encoded by the SND1 gene. SND1 is a main component of RISC complex and plays an important role in miRNA function. SND1 is Tudor domain containing protein and Tudor Proteins are highly conserved proteins and even present in Drosophila melanogaster. SND1 is also involved in Autism.

KDM4A Lysine-specific demethylase 4A is an enzyme that in humans is encoded by the Kdm4a gene

Lysine-specific demethylase 4A is an enzyme that in humans is encoded by the KDM4A gene.

Protein methylation is a type of post-translational modification featuring the addition of methyl groups to proteins. It can occur on the nitrogen-containing side-chains of arginine and lysine, but also at the amino- and carboxy-termini of a number of different proteins. In biology, methyltransferases catalyze the methylation process, activated primarily by S-adenosylmethionine. Protein methylation has been most studied in histones, where the transfer of methyl groups from S-adenosyl methionine is catalyzed by histone methyltransferases. Histones that are methylated on certain residues can act epigenetically to repress or activate gene expression.

H3K4me3 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the tri-methylation at the 4th lysine residue of the histone H3 protein and often involved in the regulation of gene expression. The name denotes the addition of three methyl groups (trimethylation) to the lysine 4 on the histone H3 protein.

H3K14ac is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the acetylation at the 14th lysine residue of the histone H3 protein.

H3R42me is an epigenetic modification to the DNA packaging protein histone H3. It is a mark that indicates the mono-methylation at the 42nd arginine residue of the histone H3 protein. In epigenetics, arginine methylation of histones H3 and H4 is associated with a more accessible chromatin structure and thus higher levels of transcription. The existence of arginine demethylases that could reverse arginine methylation is controversial.

H3R17me2 is an epigenetic modification to the DNA packaging protein histone H3. It is a mark that indicates the di-methylation at the 17th arginine residue of the histone H3 protein. In epigenetics, arginine methylation of histones H3 and H4 is associated with a more accessible chromatin structure and thus higher levels of transcription. The existence of arginine demethylases that could reverse arginine methylation is controversial.

H3R26me2 is an epigenetic modification to the DNA packaging protein histone H3. It is a mark that indicates the di-methylation at the 26th arginine residue of the histone H3 protein. In epigenetics, arginine methylation of histones H3 and H4 is associated with a more accessible chromatin structure and thus higher levels of transcription. The existence of arginine demethylases that could reverse arginine methylation is controversial.

H3R8me2 is an epigenetic modification to the DNA packaging protein histone H3. It is a mark that indicates the di-methylation at the 8th arginine residue of the histone H3 protein. In epigenetics, arginine methylation of histones H3 and H4 is associated with a more accessible chromatin structure and thus higher levels of transcription. The existence of arginine demethylases that could reverse arginine methylation is controversial.

H3R2me2 is an epigenetic modification to the DNA packaging protein histone H3. It is a mark that indicates the di-methylation at the 2nd arginine residue of the histone H3 protein. In epigenetics, arginine methylation of histones H3 and H4 is associated with a more accessible chromatin structure and thus higher levels of transcription. The existence of arginine demethylases that could reverse arginine methylation is controversial.

H4R3me2 is an epigenetic modification to the DNA packaging protein histone H4. It is a mark that indicates the di-methylation at the 3rd arginine residue of the histone H4 protein. In epigenetics, arginine methylation of histones H3 and H4 is associated with a more accessible chromatin structure and thus higher levels of transcription. The existence of arginine demethylases that could reverse arginine methylation is controversial.

References

  1. 1 2 3 4 5 6 7 8 9 10 11 Botuyan MV, Mer G (2016). "Tudor Domains as Methyl-Lysine and Methyl-Arginine Readers". Chromatin Signaling and Diseases. Elsevier. pp. 149–165. doi:10.1016/b978-0-12-802389-1.00008-3. ISBN   978-0-12-802389-1.
  2. 1 2 Lu R, Wang GG (November 2013). "Tudor: a versatile family of histone methylation 'readers'". Trends in Biochemical Sciences. 38 (11): 546–55. doi:10.1016/j.tibs.2013.08.002. PMC   3830939 . PMID   24035451.
  3. ↑ Yang Y, Lu Y, Espejo A, Wu J, Xu W, Liang S, Bedford MT (December 2010). "TDRD3 is an effector molecule for arginine-methylated histone marks". Molecular Cell. 40 (6): 1016–23. doi:10.1016/j.molcel.2010.11.024. PMC   3090733 . PMID   21172665.
  4. ↑ Cai L, Rothbart SB, Lu R, Xu B, Chen WY, Tripathy A, et al. (February 2013). "An H3K36 methylation-engaging Tudor motif of polycomb-like proteins mediates PRC2 complex targeting". Molecular Cell. 49 (3): 571–82. doi:10.1016/j.molcel.2012.11.026. PMC   3570589 . PMID   23273982.
  5. 1 2 3 4 5 6 7 8 9 10 11 Pek JW, Anand A, Kai T (July 2012). "Tudor domain proteins in development". Development. 139 (13): 2255–66. doi: 10.1242/dev.073304 . PMID   22669818. S2CID   26275277.
  6. 1 2 Ying M, Chen D (January 2012). "Tudor domain-containing proteins of Drosophila melanogaster". Development, Growth & Differentiation. 54 (1): 32–43. doi:10.1111/j.1440-169x.2011.01308.x. PMID   23741747. S2CID   23227910.
  7. ↑ Ozboyaci M, Gursoy A, Erman B, Keskin O (March 2011). "Molecular recognition of H3/H4 histone tails by the tudor domains of JMJD2A: a comparative molecular dynamics simulations study". PLOS ONE. 6 (3): e14765. Bibcode:2011PLoSO...614765O. doi: 10.1371/journal.pone.0014765 . PMC   3064570 . PMID   21464980.
  8. ↑ Botuyan MV, Lee J, Ward IM, Kim JE, Thompson JR, Chen J, Mer G (December 2006). "Structural basis for the methylation state-specific recognition of histone H4-K20 by 53BP1 and Crb2 in DNA repair". Cell. 127 (7): 1361–73. doi:10.1016/j.cell.2006.10.043. PMC   1804291 . PMID   17190600.
  9. ↑ Huang Y, Fang J, Bedford MT, Zhang Y, Xu RM (May 2006). "Recognition of histone H3 lysine-4 methylation by the double tudor domain of JMJD2A". Science. 312 (5774): 748–51. Bibcode:2006Sci...312..748H. doi:10.1126/science.1125162. PMID   16601153. S2CID   20036710.
  10. ↑ Lee J, Thompson JR, Botuyan MV, Mer G (January 2008). "Distinct binding modes specify the recognition of methylated histones H3K4 and H4K20 by JMJD2A-tudor". Nature Structural & Molecular Biology. 15 (1): 109–11. doi:10.1038/nsmb1326. PMC   2211384 . PMID   18084306.
  11. ↑ Sprangers R, Groves MR, Sinning I, Sattler M (March 2003). "High-resolution X-ray and NMR structures of the SMN Tudor domain: conformational variation in the binding site for symmetrically dimethylated arginine residues". Journal of Molecular Biology. 327 (2): 507–20. doi:10.1016/s0022-2836(03)00148-7. PMID   12628254.
  12. ↑ Rogne M, Landsverk HB, Van Eynde A, Beullens M, Bollen M, Collas P, Küntziger T (December 2006). "The KH-Tudor domain of a-kinase anchoring protein 149 mediates RNA-dependent self-association". Biochemistry. 45 (50): 14980–9. doi:10.1021/bi061418y. PMID   17154535.
  13. ↑ Caudy AA, Ketting RF, Hammond SM, Denli AM, Bathoorn AM, Tops BB, et al. (September 2003). "A micrococcal nuclease homologue in RNAi effector complexes". Nature. 425 (6956): 411–4. Bibcode:2003Natur.425..411C. doi:10.1038/nature01956. PMID   14508492. S2CID   4410688.
  14. ↑ Yoo BK, Santhekadur PK, Gredler R, Chen D, Emdad L, Bhutia S, et al. (May 2011). "Increased RNA-induced silencing complex (RISC) activity contributes to hepatocellular carcinoma". Hepatology. 53 (5): 1538–48. doi:10.1002/hep.24216. PMC   3081619 . PMID   21520169.
  15. ↑ Yoo BK, Emdad L, Lee SG, Su ZZ, Santhekadur P, Chen D, et al. (April 2011). "Astrocyte elevated gene-1 (AEG-1): A multifunctional regulator of normal and abnormal physiology". Pharmacology & Therapeutics. 130 (1): 1–8. doi:10.1016/j.pharmthera.2011.01.008. PMC   3043119 . PMID   21256156.
  16. ↑ Liu K, Chen C, Guo Y, Lam R, Bian C, Xu C, et al. (October 2010). "Structural basis for recognition of arginine methylated Piwi proteins by the extended Tudor domain". Proceedings of the National Academy of Sciences of the United States of America. 107 (43): 18398–403. Bibcode:2010PNAS..10718398L. doi: 10.1073/pnas.1013106107 . PMC   2972943 . PMID   20937909.
  17. ↑ Santhekadur PK, Das SK, Gredler R, Chen D, Srivastava J, Robertson C, et al. (April 2012). "Multifunction protein staphylococcal nuclease domain containing 1 (SND1) promotes tumor angiogenesis in human hepatocellular carcinoma through novel pathway that involves nuclear factor κB and miR-221". The Journal of Biological Chemistry. 287 (17): 13952–8. doi: 10.1074/jbc.M111.321646 . PMC   3340184 . PMID   22396537.
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